Melanocortins are neuropeptides that arise from pro-opiomelanocortin (POMC), which is most prevalently expressed in the arcuate nucleus of the hypothalamus, pituitary lobes, and the nucleus tractus solarius of the brainstem. [Gantz, I., et al., Molecular Cloning, Expression, and Gene Localization of a Fourth Melanocortin Receptor, J. Biolog. Chem., 1993, 268, 15174-15179.] These peptides include ACTH, α-MSH, β-MSH, γ1-3-MSH, and synthetic analogue NDP-αMSH (Wikberg, J E S, Melanocortin receptors: new opportunities in drug discovery, Exp. Opin. Ther. Patents, 2000, 11(1), 61-76).
These peptides bind to five types of melanocortin receptors (MC1-MC5), which are G-protein coupled receptors that all positively modulate adenylate cyclase. The MC4 and MC5 receptors are widely distributed in the brain and spinal cord, whereas the MC3 receptor is located mainly in the hypothalamus. [Gantz, I., et al., supra.] The MC4 receptor is selectively activated by αMSH and can induce neurite outgrowth in Neuro 2A cells. (Adan R. A. H, et al., Molecular Brian Research, 1996, 36, pp 37-44; Mountjoy, K. G., Mortud, M. T., Low, M. J., Simerly, R. B. and Cone, R. D., Mol. Endocrinol., 1994, 8, pp 1298-1308). ACTH is a less potent activator of the MC4 receptor than α-MSH. (Adan, R. A. H., Cone, R. D., Burbach, J. P. H. and Gispen, W. H., mol. pharmacol., 1994, 46, pp 1182-1190). The MC5 receptor is activated, in order of degree, by NDP-α-MSH>ACTH (1-24)≧α MSH ACHT (1-39)=β MSH>>γMSH (The Melanocortin Receptors, Cone, R. D., Editor, Human Press Inc., Totowa, N.J., 2000, Chen, W., pp 449-472)
The melanocortins αMSH and ACTH are also known for their ability to stimulate pigmentation and adrenal glucocorticoid secretion, respectively. The role of melanocortins, particularly αMSH, in the regulation of sebaceous gland activity (an exocrine gland with holocrine type of secretion) was shown originally in rats. More particularly, the studies showed that removal of the intermediate lobe of the pituitary (which produces the POMC peptides) resulted in decreased sebaceous lipid production, with complete restoration to normal levels after replacement therapy with αMSH (Thody, A. J. and Shuster, Nature, 237, 346-347, 1972). In a study of rats following total hypophysectomy, treatment with αMSH resulted in an increase of sebum production, although full restoration of sebum production was achieved only after treatment with a combination of GASH and testosterone (Thody, A. J., Shuster, S., J. Endocr. 64, 503-510, 1975; Ebling, F. J., Ebling, E., Randall, V. and Skinner, J., J. Endocr. 66, 407-412, 1975). Knock-out mice where the MC5 receptor was deleted were observed to display a severe defect in water repulsion and thermo-regulation, due to decreased production of sebaceous lipids (Chen, W. Kelly, M. A., Opitz-Araya, X., Thomas, R. E., Low, M. J., and Cone, R., Cell, 91, 788-798, 1997).
The MC5 receptor is known to be expressed in human sebaceous glands, and may be involved in the regulation of human sebaceous lipid synthesis. The human MC5 receptor has been cloned and characterized (Chhajlani, V., Muceniece, R., Wikberg, JES., Biochem. Biophys. Res. Commun. 195, 866-873, 1993). Moreover, presence of MC5 receptor m RNA in human sebaceous glands has been shown by RT-PCR and the protein was detected by immunohistochemistry and Western blot analysis (Thiboutot, D., Sivarajah, Gililand, K., Cong, Z. and Clawson, G., J. Invest. Dermatol. 115(4), 614-619, 2000).
Human sebum differs in its composition from other mammals. The main lipids in human sebum are triglycerides, wax esters and squalene (Greene, R. S., Downing, D. T., Poci, P. E., Strauss, J. S., JID 54, 240-247, 1970).
Squalene, for instance, is not found in many mammals with the exception of otter and beaver. Triglycerides, which are a major component of human sebum, are poorly represented in other species and in many (e.g. chimpanzee) appear to be totally absent (Thody, A. J., Shuster, S., Physiolog. Rev. 69, 383-415, 1989). Moreover, melanocortins can have different effects on cells from different species. For example both αMSH (EC50=3.7 nM) and ACTH (EC50=16.4 nM) are potent lipolytic agents for rabbit adipocytes, whereas in the rat only ACTH (EC50=1.34 nM) has potent lipolytic activity (Ramachadran, J., Lee, V., 428, 339-346, 1987; Richter, W. O., Schwandt, P., Neuropeptides 9, 59-74, 1987). Despite lipolytic activity in rodents and rabbits, ACTH has very little effect on lipolysis in isolated human and non-human primate adipocytes, even at concentrations as high as 1 μM (Ng, T. B. Comparative Biochem. 97, 441-446, 1990). Thus defining the role of melanocortins and their receptors in animal sebaceous model systems is not necessarily predictive of their role in a human sebaceous lipid regulation.
Eisinger, M., et al., in U.S. Pat. No. 7,049,331, issued May 23, 2006 disclose 1,2,4-thiadiazole derivatives useful as melanocortin receptor modulators. Eisinger, M., et al., in U.S. Pat. No. 7,319,107, issued Jan. 15, 2008 disclose thiadiazolium derivatives useful as melanocortin receptor modulators.